A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

ChauhanD.; TianZ.; NicholsonB.; KumarK.G.S.; ZhouB.; CarrascoR.; McDermottJ.L.; LeachC.A.; FulcinnitiM.; KodrasovM.P.; WeinstockJ.; KingsburyW.D.; HideshimaT.; ShahP.K.; MinvielleS.; AltunM.; KesslerB.M.; OrlowskiR.; RichardsonP.; MunshiN.; AndersonK.C.

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A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

机译：泛素特异性蛋白酶7的小分子抑制剂诱导多发性骨髓瘤细胞凋亡并克服硼替佐米耐药性。

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Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.

机译：硼替佐米疗法已被证明可成功治疗复发/难治，复发和新诊断的多发性骨髓瘤（MM）。但是，剂量限制的毒性和耐药性的发展限制了其长期使用。在这里，我们显示P5091是去泛素化酶USP7的抑制剂，USP7可以诱导对常规和硼替佐米疗法产生耐药性的MM细胞凋亡。生化和遗传研究表明，HDM2和p21的阻滞消除了P5091诱导的细胞毒性。在动物肿瘤模型研究中，P5091具有良好的耐受性，可抑制肿瘤生长并延长生存期。将P5091与来那度胺，HDAC抑制剂SAHA或地塞米松组合可触发协同的抗MM活性。因此，我们的临床前研究支持USP7抑制剂（单独或联合使用）作为潜在的MM治疗的临床评估。

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《Cancer Cell》 |2012年第3期|共14页
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ChauhanD.; TianZ.; NicholsonB.; KumarK.G.S.; ZhouB.; CarrascoR.; McDermottJ.L.; LeachC.A.; FulcinnitiM.; KodrasovM.P.; WeinstockJ.; KingsburyW.D.; HideshimaT.; ShahP.K.; MinvielleS.; AltunM.; KesslerB.M.; OrlowskiR.; RichardsonP.; MunshiN.; AndersonK.C.;
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正文语种 eng
中图分类肿瘤学;
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1. A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance [J] . ChauhanD., TianZ., NicholsonB., Cancer Cell . 2012,第3期

机译：泛素特异性蛋白酶7的小分子抑制剂诱导多发性骨髓瘤细胞凋亡并克服硼替佐米耐药性。
2. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance [J] . Ze Tian, Padraig DArcy, Xin Wang, Blood: The Journal of the American Society of Hematology . 2014,第5期

机译：一种新型的去泛素化酶USP14和UCHL5的小分子抑制剂可诱导多发性骨髓瘤细胞凋亡并克服硼替佐米耐药性
3. Inhibition of WIP1 Phosphatase in Multiple Myeloma Overcomes Bortezomib Resistance and Promotes Cell Death Via ER Stress-Induced Apoptotic JNK/c-jun Signaling and Downregulation of Inhibitors of Apoptosis Proteins (IAPs) [J] . Beider Katia, Rosenberg Evgenia, Voevoda Valeria, Blood: The Journal of the American Society of Hematology . 2018,第NovaelaTreatmentAppr期

机译：多发性骨髓瘤中Wip1磷酸酶的抑制克服了Bortezomib抗性，通过ER应激诱导的凋亡JNK / C-Jun信号传导和凋亡蛋白抑制剂的下调促进细胞死亡（IAPS）
4. The Tricyclic Antidepressant Amitriptyline Inhibits D-Cyclin Transactivation and Induces Myeloma Cell Apoptosis by Inhibiting Histone Deacetylases: In Vitro and In Silico Evidence [C] . Xinliang Mao, Depei Wu, Suzanne Trudel, International conference of molecular simulations and applied informatics technologies . 2012

机译：三环抗抑郁药阿米替林通过抑制组蛋白脱乙酰基酶抑制D-cyclin反式激活并诱导骨髓瘤细胞凋亡：体外和计算机证据。
5. The Role of Klf9 in Cell Stress-Induced Cell Death In Normal Cells and in the Therapeutic Response of Multiple Myeloma Cells to Proteasome Inhibitors [D] . Fink, Emily 2017

机译：Klf9在正常细胞中细胞应激诱导的细胞死亡中的作用以及在多发性骨髓瘤细胞对蛋白酶体抑制剂的治疗反应中的作用
6. A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance [O] . Dharminder Chauhan, Ze Tian, Benjamin Nicholson, -1

机译：泛素特异性蛋白酶7诱导凋亡在多发性骨髓瘤细胞的小分子抑制剂和硼替佐米克服阻力
7. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. [O] . Chauhan, D, Tian, Z, Nicholson, B, 2012

机译：泛素特异性蛋白酶7的小分子抑制剂诱导多发性骨髓瘤细胞凋亡，并克服了硼替佐米的耐药性。

A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

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